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McBride
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Physician Assistant trained at State University of New York at Stony Brook. I am an Allied Fellow Member of the American Urological Association, Fellow of the American Academy of Physician Assistants, Fellow of the Urological Association of Physician Assistants, and former Vice President of the... More
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Adirondack Surgical Group
  • Here's My Argument Against Zytiga, Clinically Speaking 5 comments
    Dec 19, 2012 7:44 PM | about stocks: DNDN, JNJ

    Clinically speaking, it's not about Zytiga...that blocks hormones so high up in the pathway that it disallows production of testosterone (and other important hormones) very solidly. That is super effective in blocking all sources of androgen production!

    The drug Zytiga abiraterone which is used to treat castration-resistant prostate cancer blocks the biosynthesis of androgens by inhibiting the CYP17A1 enzyme. Abiterone binds in the active site of the enzyme and coordinates the heme iron through its pyridine nitrogen, mimicking the subtrate

    So, it is blocking the synthesis of mineralocorticoids, glucocorticoids, and Androgens and Estrogens.

    Abiraterone blocks the enzyme inhibits CYP17A1 (17α-hydroxylase) which converts pregnenolone and progesterone to their 17-hydroxy forms, and converts 17-hydroxypregnenolone and 17-hydroxyprogesterone to DHEA and androstenedione, respectively. It corresponds to the downward arrows in this reaction scheme.

    Source:

    http://en.wikipedia.org/wiki/CYP17A1

    I worry more about Zytiga's partner in crime, Prednisone. It has significant short term and long term side effects, including dependancy!

    Prednisone is a glucocorticoid ONLY. It does not give back the necessary mineralocorticoids blocked by the Zytiga, as seen above. What does this cause? A condition called hypoaldosteronism.

    The effects of hypoaldosteronism:

    This condition may result in hyperkalemia, when it is sometimes termed 'type 4 renal tubular acidosis' even though it doesn't actually cause acidosis. It can also cause urinary sodium wasting, leading to volume depletion and hypotension.

    Na+ is lost in the urine. K+ is retained, and the plasma K+ rises.

    When adrenal insufficiency develops rapidly, the amount of Na+ lost from the extracellular fluid exceeds the amount excreted in the urine, indicating that Na+ also must be entering cells. When the posterior pituitary is intact, salt loss exceeds water loss, and the plasma Na+ falls. However, the plasma volume also is reduced, resulting in hypotension, circulatory insufficiency, and, eventually, fatal shock. These changes can be prevented to a degree by increasing the dietary NaCl intake. Rats survive indefinitely on extra salt alone, but in dogs and most humans, the amount of supplementary salt needed is so large that it is almost impossible to prevent eventual collapse and death unless mineralocorticoid treatment is also instituted

    Source: http://en.wikipedia.org/wiki/Mineralocorticoid_deficiency

    I will defer to Wikipedia's entry for Prednisone, under the category of "Side Effects", with a healthy knowledge that endocrinologists are very hard to come by in the United States (shortage is described here http://www.endo-society.org/media/press/2008/Endocrinology-Workforce-Shortage-Represents.cfm as far back as 2008)

    Side-effects

    Short-term side-effects, as with all glucocorticoids, include high blood glucose levels, especially in patients with diabetes mellitus or on other medications that increase blood glucose such as tacrolimus) and mineralocorticoid effects such as fluid retention. It is worth noting, however, that the mineralocorticoid effects of prednisone are very minor; this is why it is not used in the management of adrenal insufficiency, unless a more potent mineralocorticoid is administered concomitantly.

    Additional short-term side-effects can include insomnia, euphoria and, rarely, mania (in particular, in those suffering from Bipolar disorders I and II). It can also cause depression or depressive symptoms and anxiety in some individuals.[4][5]

    Long-term side-effects include Cushing's syndrome, truncal weight gain, osteoporosis, glaucoma and cataracts, type II diabetes mellitus, and depression upon dose reduction or cessation.[citation needed]

    [edit] Major

    Question book-new.svgThis section does not cite any references or sources. Please help improve this section by adding citations to reliable sources. Unsourced material may be challenged and removed. (December 2012)


     

    [edit] Minor

    Question book-new.svgThis section does not cite any references or sources. Please help improve this section by adding citations to reliable sources. Unsourced material may be challenged and removed. (December 2012)

    [edit] Dependency

    Adrenal suppression will begin to occur if prednisone is taken for longer than seven days. Eventually, this may cause the body to temporarily lose the ability to manufacture natural corticosteroids (especially cortisol), which results in dependence on prednisone. For this reason, prednisone should not be abruptly stopped if taken for more than seven days, instead, the dosage should be gradually reduced. This weaning process may be over a few days, if the course of prednisone was short, but may take weeks or months if the patient had been on long-term treatment. Abrupt withdrawal may lead to an Addisonian crisis. For those on chronic therapy, alternate-day dosing may preserve adrenal function and thereby reduce side-effects.[6]

    Glucocorticoids act to inhibit-feedback of both the hypothalamus, decreasing corticotropin-releasing hormone [CRH], and corticotrophs in the anterior pituitary gland, decreasing the amount of adrenocorticotropic hormone [ACTH]. For this reason, glucocorticoid analogue drugs such as prednisone down-regulate the natural synthesis of glucocorticoids. This mechanism leads to dependence in a short time and can be very dangerous if medications are withdrawn too quickly. The body must have time to begin synthesis of CRH and ACTH and for the adrenal glands to begin functioning normally again.

    As you can see, the dangerous game of replacing only glucocorticoid when Zytiga blocks both glucocorticoid and mineralcorticoid production, leaves patients at risk of Prednisone side effects and dependancy, as well as putting them at risk for hypoaldosteronism. None of this should be taken lighly given the shortage of endocrinologists in the United States.

    Disclosure: I am long DNDN.

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Comments (5)
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  • Franklin D
    , contributor
    Comments (9) | Send Message
     
    I heard from someone who was in the Phase II trial of Abiraterone and has been on Zytiga for 5 years and has not suffered from any of the side effects mentioned in this article and is still responding to this drug.
    20 Dec 2012, 04:59 AM Reply Like
  • McBride
    , contributor
    Comments (410) | Send Message
     
    Author’s reply » That's wonderful, Franklin D. I had an 84 year old patient die of adrenal crisis because he was taken off his prednisone too suddenly because of a leg wound, out of fear it would make his healing process too slow. He was admitted to the hospital with no endocrinologist available to help. His doctors finally consulted with me and we worked out the need to have him back on high dose prednisone, PLUS add a mineralocorticoid. It's not necessarily the Zytiga/abiraterone, it's the often misunderstood and underdiagnosed issues surrounding the prednisone-only approach to replacing the lost glucocorticoid, but ignoring the mineralocorticoid suppression- hypoaldosteronism.

     

    Chances are your 5 year patient has been perfectly followed, which is great.
    20 Dec 2012, 12:25 PM Reply Like
  • Gordon38
    , contributor
    Comment (1) | Send Message
     
    I have been taking Zytiga and prednisone for a year now. My PSA plummeted to zero in 3 week from 27 and 5 painful lesions in my spine were radiated. I have no back pain and am able to run 3 or 4 miles a day. My sleep is sometimes difficult. I get a jittery feeling with some tremor for a few hours in the afternoon which I attribute to the prednisone. My labs are good. On the whole I feel great. I owe this respite from my cancer to Zytiga.
    7 Oct 2013, 04:01 PM Reply Like
  • McBride
    , contributor
    Comments (410) | Send Message
     
    Author’s reply » Awesome! Great to hear you had a good outcome, from PSA 27 to 0. You said you were on Zytiga and prednisone, for how long before the PSA went from 27 to 0? Was it timed with the radiation therapy? The radiation to the bone is gold standard, and the powerful anti-androgen Zytiga seems to be doing its work. Just curious, has your doctor put you on Prolia or Xgeva as well? These are indicated to help with bone loss (osteoclastic) activity from anti-androgens. And if you don't mind disclosing, what is your current dose of Prednisone?
    13 Oct 2013, 11:29 AM Reply Like
  • McBride
    , contributor
    Comments (410) | Send Message
     
    Author’s reply » The ultimate goal with prednisone replacement is to avoid this disease, article from Wikipedia about Adrenal insufficiency.

     

    It appears the patient I described in my OP died from a critical illness-related corticosteroid deficiency.

     

    http://bit.ly/GXRawW
    13 Oct 2013, 11:37 AM Reply Like
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